The long term objective of this project is to develop single-photon emitting receptor binding radiotracers and implement methods for quantitating SPECT images of receptors in the brains of patients suffering from a variety of disorders which have been shown to affect receptor systems in the CNS. We are currently investigating the muscarinic acetylcholine receptor (m-AChR) with respect to changes in Alzheimer's disease and related disorders. Although this is a new proposal, we have imaged m-AChR in man using (R,R) (123I) 3-quinuclidinyl 4-iodobenzilate (41QNB), a high affinity m-AChR antagonist which we developed for myocardial imaging. But it is better suited for use in the CNS because there is a need for diagnostic tools which which provide information on receptor concentrations in brain. The objectives of this current proposal are to prepare in large quantities the precursor for synthesis of (R,R) and (R,S) (123I) 41QNB for use in clinical and biochemical studies. The (R,S) diastereomer provides different kinetic properties from those of the (R,R) diastereomer which may be more beneficial for the clinical studies. The clinical studies are suggested for a five year period; the patient populations to be examined are those with Alzheimer's disease, multi infarct dementia and Parkinson's disease. Normal subjects, age and sex matched, will be recruited from the families of patients when possible. The biochemical studies are designed to demonstrate that receptor concentration changes can be measured by the in vivo distribution of 41QNB. Changes are effected by a variety of lesioning techniques and the demonstration mapping by autoradiography. We will also establish the metabolic fate of (125I) 41QNB and the effect of decay on the compound and its receptor. In addition, we will provide the synthetic route for the synthesis of (11C) 3-quinuclidinyl atrolactate, a positron emitting radiotracer with many of the same properties as 41QNB. We will compare and contrast the images obtained using the two different radionuclides and technologies for their detection. The long term results of our pursuit of these goals will be an agent or agents which will be used for determining the change of receptor concentration of receptors in the CNS related to disease.